Studies of interferon (IFN)-dependent gene expression have led to the elucidation of pathways that signal directly from the cell surface to the nucleus. The Signal Transducers and Activators of Transcription (STATs) are essential mediators of signaling in these direct pathways. The STATS comprise a family of transcription factors that are activated by tyrosine kinases in the cytoplasm and then migrate to the nucleus where they directly regulate gene expression.
Seven mammalian STAT family members (Stat1-Stat6, with STAT5a and STAT5b representing distinct genes) have been molecularly cloned and share common structural elements, including a Src-homology 2 (SH2) domain. Monomeric, inactive STAT proteins associate with each other to form active dimers through a key phosphotyrosine (pY) residue, which binds to the SH2 domain of another STAT monomer. Reciprocal SH2-pY interactions are critical for STAT functions, including nuclear transport and DNA binding. The DNA-binding domain resides in the N-terminal portion of the STAT molecule (Horvath, et al., 1995, Genes Dev. 9:984-994). Located within the C-terminal portion is the transactivation domain, which contains critical serine residue, the phosphorylation of which is required for maximal transcriptional activity.
The signal cascade initiates when cytokines (such as IFNs and members of the interleukin family) or growth factors (epidermal growth factor and platelet-derived growth factor, for example) bind to their cognate cell surface receptors. Certain growth factor receptors possess intrinsic tyrosine kinase activity and phosphorylate STATs directly, thereby activating STAT signaling. In contrast, cytokine receptors lack intrinsic kinase activity, and recruit members of the Janus kinase (JAK) family of cytoplasmic tyrosine kinases to activate STATs. JAK family kinases have been shown to be involved in STAT activation (Ihle & Kerr, 1995, Trends in Genetics, 11:69-74). Depending on which STAT family members are activated, STATs may associate as homodimers or heterodimers, and then translocate to the nucleus, whereupon the activated STAT dimers bind to specific DNA-response elements in promoters, and induce expression of target genes.
Certain non-STAT3 STAT proteins and chimeric peptides derived from them were described by Darnell, Jr., et al. (U.S. Pat. No. 5,716,622, published Feb. 10, 1998). In related patents, further non-STAT3 STAT DNA sequences were disclosed, and chimeric STAT proteins were claimed (U.S. Pat. Nos. 5,883,228, published Mar. 16, 1999; U.S. Pat. No. 5,976,835, published Nov. 2, 1999). Thus, the STAT proteins appear to have a role in the regulation of cell growth. Constitutive activation of various members of the STAT family has been reported in different cell lines. The present invention significantly extends the characterization of STAT3's role in growth regulation and ocogenesis, beyond those described previously, and establishes rationale for modulation of STAT3 signaling for the purpose of treating patients with cancerous conditions. The present invention addresses that need by advancing means for such regulation.